The invention relates to new arylglycinamide derivatives of general formula 
and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin) antagonists.
The abbreviations used in this specification and claims are explained as follows:
CDI=Carbonyldiimidazole
DCCI=Dicyclohexylcarbodiimide
HOBt=1-Hydroxybenzotriazole
THF=Tetrahydrofuran
DMF=Dimethylformamide
RT=Room temperature
DMAP=4-Dimethylaminopyridine
TBTU=O-Benzotriazolyl-tetramethyluronium-tetrafluoroborate
The formulae are shown in simplified form. In representing the compounds, for example, all the CH3-substituents are represented by a hyphen and CH is represented by , thus, for example: 
denotes 
The invention relates to new arylglycinamide derivatives of general formula I 
or the pharmaceutically acceptable salts thereof, wherein
Ar denotes unsubstituted or mono- to penta-substituted phenyl, or unsubstituted or mono- or disubstituted naphthyl [wherein the substituents of the phenyl and naphthyl independently of one another denote halogen (F, Cl, Br, I), (C1-4)alkyl, Oxe2x80x94(C1-4)alkyl, CF3, OCF3 or NR12R13 (wherein R12 and R13 independently of one another denote H, methyl or acetyl)] or Ar is phenyl substituted by xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94or xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94;
R1 and R2 together with the N to which they are bound denote a ring of the formula 
or 
wherein
r, s and t are 2 or 3;
R6 denotes
H.
(C1-5)alkyl,
(C3-5)alkenyl
propynyl,
hydroxy (C2-4)alkyl,
methoxy(C2-4)alkyl,
di (C1-3)alkylamino (C2-4)alkyl,
amino (C2-4)alkyl,
amino,
di(C1-3)alkylamino,
monofluoro- to perfluoro(C1-2)alkyl,
N-methylpiperidinyl,
pyridyl,
pyrimidinyl,
pyrazinyl,
pyridazinyl
or the group xe2x80x94CH2xe2x80x94C(O)NR14R15,
wherein
R14 is H or (C1-4)alkyl and
R15 is H, (C1-4)alkyl, (C3-6)cycloalkyl, hydroxy(C2-4)alkyl, alkoxy(C2-3)alkyl, phenyl(C1-4)alkyl, or R14 and R15 together with the N to which they are bound form a ring (1-pyrrolidinyl, piperidino, morpholino or 1-methylpiperazin-4-yl);
R7 has one of the definitions (a) to (d),
(a) hydroxy
(b) 4-piperidinopiperidyl,
(c) 
wherein R16 and R17 independently of one another denote
H,
(C1-4)alkyl,
(C3-6)cycloalkyl,
hydroxy (C2-4)alkyl,
(C1-3) alkoxy(C2-4)alkyl,
phenyl(C1-4)alkyl or
di(C1-3)alkylamino(C2-4)alkyl,
or if R16 is H or (C1-4)alkyl,
R17 may also be xe2x80x94CH2C(O)NR18R19, wherein R18 and R19 are defined as R14 and R15 hereinbefore;
(d) 
wherein R20 denotes
H,
(C1-4)alkyl,
(C4-6)cycloalkyl or
xe2x80x94CH2C(O)NR21R22,
wherein R21 and R22 are defined as R14 and R15 
hereinbefore;
R8 is H
R9 and R10 independently of each other denote (C1-4)alkyl;
R11 denotes
H,
(C1-5)alkyl,
(C3-5)alkenyl,
propynyl,
hydroxy(C2-4)alkyl,
methoxy(C2-3)alkyl,
di (C1-3)alkylamino (C2-3)alkyl,
amino(C2-3)alkyl,
amino,
di(C1-3)alkylamino,
monofluoro- to perfluoro (C1-2)alkyl,
N-methylpiperidinyl,
pyridyl,
pyrimidinyl,
pyrazinyl,
pyridazinyl
or the group xe2x80x94CH2xe2x80x94C(O)NR23R24,
wherein R23 and R24 are defined as R14 and R15 hereinbefore;
R3 denotes H, (C1-4)alkyl, unsubstituted or mono- to trisubstituted phenyl, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C1-4)alkyl, Oxe2x80x94(C1-4)alkyl, CF3, OCF3 or NR25R26 (wherein R25 and R26 independently of one another denote H, methyl or acetyl);
R4 denotes phenyl(C1-4)alkyl or naphthyl(C1-4)alkyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C1-4)alkyl, Oxe2x80x94(C1-4)alkyl, CF3, OCF3 or NR27R28 (wherein R27 and R28 independently of one another denote H, methyl or acetyl); and
R5 denotes H, (C1-4)alkyl, (C3-6)cycloalkyl, CH2COOH, CH2C(O)NH2, OH or phenyl(C1-4)alkyl.
Preferred compounds of general formula I are those wherein
Ar denotes unsubstituted or mono- or disubstituted phenyl, or unsubstituted naphthyl, or Ar is phenyl substituted by xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94;
R1 and R2 together with the N to which they are bound denote a ring of the formula 
or 
wherein
r is 2 or 3 and
s and t are 2;
R6, R7, R8, R9, R10 and R11 are as hereinbefore defined;
R3 is H or (C1-4)alkyl,
R4 denotes phenyl(C1-4)alkyl or naphthyl(C1-4)alkyl, wherein phenyl may be substituted by 1 or 2 substituents, wherein the substituents independently of one another are halogen (F, Cl, Br, I), (C1-4)alkyl, Oxe2x80x94(C1-4)alkyl, CF3 or OCF3; and
R5 denotes H, (C1-4)alkyl, (C3-6)cycloalkyl, OH or (C1-4)alkylphenyl.
Particular mention should be made of compounds of formula I wherein
Ar is unsubstituted or mono- or disubstituted phenyl, or unsubstituted naphthyl [wherein the substituents of the phenyl independently of one another are halogen (F, Cl, Br, I), methyl, methoxy, CF3 or OCF3] or Ar is phenyl substituted by xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94;
particularly those wherein Ar is phenyl, naphthyl, phenyl substituted in position 3 and/or 4 by methoxy or halogen, or phenyl in which positions 2 and 3 or 3 and 4 are linked by xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, preferably those compounds wherein
Ar is phenyl,
phenyl substituted by methoxy in positions 3 and 4 or phenyl wherein positions 3 and 4 or 2 and 3 are linked by xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94.
Of the compounds defined above, special mention should be made of those wherein, in the ring 
r is 2 or 3 and
R6 denotes
H,
(C1-5)alkyl,
(C3-5)alkenyl,
propynyl,
hydroxy (C2-4)alkyl,
methoxy (C2-4)alkyl,
di(C1-3)alkylamino(C2-4)alkyl,
amino (C2-4)alkyl,
amino,
di(C1-3)alkylamino,
monofluoro- to perfluoro(C1-2)alkyl,
N-methylpiperidinyl,
pyridyl,
pyrimidinyl, or 
particularly those wherein
r is 3 and R6 is methyl;
and those wherein
r is 2 and
R6 is
H,
(C1-4)alkyl,
propenyl,
propynyl,
hydroxy (C2-3)alkyl,
methoxyethyl,
di(C1-2)alkylamino (C2-3)alkyl,
aminoethyl,
amino,
dimethylamino,
CH2CF3,
N-methylpiperidinyl,
pyridyl,
pyrimidinyl, or 
preferably those wherein
r is 2 and
R6 is H, (C1-3)alkyl, allyl, 2-propynyl, xe2x80x94CH2CH2OCH3, xe2x80x94CH2CH2N(CH3)2, N-methylpiperidinyl, 2-pyrimidinyl or 
r is 2 and
R6 is H, CH3, C3H7, CH(CH3)2, CH2CH2OH, CH2CH2OCH3 or CH2CH2N (CH3)2.
Of the compounds defined above, mention should also be made of those wherein R1 and R2 together with the N to which they are bound form the ring 
wherein R8 is H and
R7 is OH 
wherein R16 and R17 independently of one another denote:
H
(C1-3)alkyl, 
(CH2)nOH wherein n is 2, 3 or 4
(CH2)2OCH3 
xe2x80x94(CH2)nPh wherein n is 2 or 4
(CH2)2N(CH3)2 
particularly those wherein
R16 and R17 are both CH3 or C2H5 or
R16 is H or CH3 and R17 is (C1-3)alkyl, 
(CH2)2OH,
(CH2)4OH or 
and those wherein
R7 denotes 
especially those wherein
R1 and R2 together with the N to which they are bound form the ring 
xe2x80x83wherein
(a) R8 is H and
R7 is 
wherein R16 and R17 both represent CH3, C2H5 or CH2CH2OH or R16 is H or CH3 and R17 is (C1-3)alkyl, 
(CH2)2OH or
(CH2)4OH or
(b) R8 is H and R7 denotes 
Of the compounds defined above, mention should also be made of those wherein
R1 and R2 together with the N to which they are bound form the ring 
Of the compounds defined above, special mention should also be made of those wherein
R1 and R2 together with the N to which they are bound form the ring 
wherein R11 is H or (C1-3)alkyl, particularly those wherein
R11 is xe2x80x94CH(CH3)2 
Of the compounds defined above, the ones of particular interest are those wherein R3 is H; and/or
R4 denotes phenyl(C1-4)alkyl, wherein phenyl may be substituted by 1 or 2 substituents, wherein the substituents independently of one another denote halogen (F, Cl, Br, I), (C1-4)alkyl, Oxe2x80x94(C1-4)alkyl, CF3 or OCF3; and/or
R5 denotes H, (C1-4)alkyl, (C3-6)cycloalkyl, xe2x80x94OH or phenyl(C1-4)alkyl,
particularly those wherein
R4 denotes phenyl(C2-4)alkyl, wherein the substituents are in positions 3 and/or 5 of the phenyl ring and/or
R5 is H, methyl, OH or phenethyl, preferably those wherein
R4 is 
and R5 is methyl.
Compounds of general formula I may have acid groups, chiefly carboxyl groups, and/or basic groups such as amino functions, for example. Compounds of general formula I may therefore be present either as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically acceptable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as dimethylamine, triethylamine, triethanolamine, etc.
The compounds according to the invention may occur as racemates but may also be obtained as pure enantiomers, i.e. in the (R)- or (S)-form.
The term naphthyl used hereinbefore includes both 1-naphthyl and 2-naphthyl.
Test results for compounds according to the invention:
The receptor affinity for the NK1-receptor (substance P-receptor) is determined on human lymphoblastoma cells (IM-9) with cloned NK1-receptors, by measuring the displacement of 125I-labelled substance P. The Ki-values thus obtained show the efficacy of the compounds:
The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P antagonism and also neurokinin A and neurokinin B antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases:
for the treatment or prevention of inflammatory and allergic diseases of the respiratory tract, such as asthma, chronic bronchitis, hyperreactive respiratory tract, emphysema, rhinitis and cough,
and of the eyes, such as conjunctivitis and iritis,
of the skin, such as dermatitis in contact eczema, urticaria, psoriasis, sunburn, insect bites and stings, itching, sensitive or hypersensitive skin,
of the gastrointestinal tract, such as gastric and duodenal ulcers, ulcerative colitis, Crohn""s disease, irritable bowel and Hirschsprung""s disease,
of the joints, such as rheumatoid arthritis, reactive arthritis and Reiter syndrome;
for treating diseases of the central nervous system such as dementia, Alzheimer""s disease, schizophrenia, psychoses, depression, headache (e.g. migraine or tension headaches), epilepsy, Parkinson""s disease and stroke;
for treating herpes zoster and postherpetic pain, tumours, collagenoses, dysfunction of the deferent urinary tract, haemorrhoids, nausea and vomiting, caused for example by radiation or cytostatic therapy or motion and pain of all kinds.
The invention therefore also relates to the use of the compounds according to the invention as therapeutic agents and pharmaceutical preparations which contain these compounds. They are preferably used in humans. The compounds according to the invention may be administered by intravenous, subcutaneous, intramuscular, intraperitoneal or intranasal route, by inhalation, by transdermal route, optionally aided by iontophoresis or enhancers known from the literature, and by oral route.
For parenteral administration the compounds of formula I or the physiologically acceptable salts thereof, possibly with the conventional substances such as solubilisers, emulsifiers or other adjuvants, are dissolved, suspended or emulsified. Solvents which may be used include: water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of several solvents.
In addition, the compounds may be administered by means of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations.
The oral efficacy of compounds of general formula I can be demonstrated by the following standard test:
Inhibition of lowering of blood pressure caused by NK1 in anaesthetised guinea pigs.
Guinea pigs weighing 300-500 grams were anaesthetised with pentobarbital (50 mg/kg i.p.), intubated and artificially ventilated. They were ventilated with 10 ml/kg of air at a frequency of 60 breaths per minute. The carotid artery was canulated and the arterial blood pressure was recorded. A polyethylene tube was inserted into the jugular vein for the intravenous supply of substances.
A temporary reduction in blood pressure was brought about at intervals of 10 minutes by intravenous administration of the NK1-agonist [(xcex2Ala4, Sar9, Met (O2)11]SP (4-11) 
in a dose of 0.2 xcexcmol/kg. After the blood pressure thus produced has been measured, the test compound was introduced into the duodenum and the NK1-agonist was again injected every 10 minutes.
The results were expressed as a % inhibition of the reduction in blood pressure caused by the NK1-agonist specified.
In a dosage of 1 mg/kg (administered into the duodenum) the compound of Example 1 inhibited the lowering of blood pressure caused by the NK1-agonist by 80%.
The compounds according to the invention can be produced using generally known methods.
The compounds may be prepared in various ways. The two most common procedures are represented by the following diagram: 
Method A. The carboxylic acid may be linked to the amine HN(R5)R4 by various methods. Conventional methods are coupling processes such as those used in peptide chemistry. A coupling reagent such as TBTU, DCCI/HOBt, CDI, etc., is added to the coupling partners in substantially equivalent quantities. Suitable solvents are DMF, THF, CH2Cl2, CHCl3, acetonitrile or other inert solvents or mixtures thereof. The suitable temperature range is between xe2x88x9250xc2x0 C. and +120xc2x0 C., preferably between 0xc2x0 C. and 40xc2x0 C.
The carboxylic acid may also initially be converted into the corresponding acid halide by known methods using SOCl2, SO2Cl2, PCl3, PCl5 or PBr3 or mixtures thereof, and the acid halide is then reacted with the amine HN(R5)R4 in an inert solvent such as CH2Cl2, THF or dioxane at temperatures between xe2x88x9250xc2x0 C. and +100xc2x0 C., typically at 0xc2x0 to 20xc2x0 C.
Another alternative is to convert the carboxylic acid initially into the alkylester, usually the methylester, by known methods and this ester is then reacted with the amine HN(R5)R4 in an inert solvent such as DMF, dioxane or THF. The reaction temperatures are between 20xc2x0 C. and 150xc2x0 C., typically between 50xc2x0 C. and 120xc2x0 C. The reaction may also be carried out in a pressurized container.
Method B. Here, the xcex1-halo-arylacetamide derivative obtained by known methods is reacted with the amine R1(R2)NH, thereby cleaving hydrogen halide. Inorganic bases such as K2CO3, NaHCO3 or CaCO3 or organic bases such as triethylamine, Hxc3xcnig base, pyridine or DMAP are used to mop up the cleaved (or excess) hydrogen halide, or an excess of the amine R1 (R2)NH may be used. DMF, THF, dioxane or other inert solvents are used. The temperature range for the reaction is from 0 to 100xc2x0 C., typically between 10 and 80xc2x0 C.
Method C. The compounds according to the invention wherein R5 is not H may also be prepared as follows: first of all, the corresponding compound in which R5 is H is synthesised using method A or B. Then, N-alkylation is carried out as follows in order to introduce alkyl, cycloalkyl or CH2COOH. The compounds according to the invention wherein R5 is H are deprotonated with an equivalent quantity of NaH, NaNH2, KOH, NaOCH3 or another strong base. Anhydrous inert solvents such as THF, dioxane or diethylether are used for this. Then the corresponding alkylating agent is added slowly in the form of the corresponding halide, tosylate or mesylate. The reaction is carried out at a temperature within the range from xe2x88x9250xc2x0 C. to +100xc2x0 C., typically between 0xc2x0 C. and +5xc2x0 C.